RESUMO
The RTK/RAS pathway is an oncogenic signaling pathway for which many targeted drugs have been developed; however, survival remains poor. A combination of targeted therapy and immunotherapy has emerged as an option for improving cancer treatment responses. In this study, on the basis of the expression, survival, single nucleotide variation (SNV), copy number variation (CNV), and methylation data of lung adenocarcinoma (LUAD) from The Cancer Genome Atlas database, we comprehensively analyzed the genomic changes in the RTK/RAS pathway and their associations with tumor-infiltrating lymphocytes (TIL) and prognosis in LUAD to provide the genomics landscape of RTK/RAS with TIL and prognosis. We found that two rarely mutated genes, mitogen-activated protein kinase kinase 1 and insulin-like growth factor 1 receptor, were significantly associated with the worse survival of patients with LUAD. Patients with LUAD and co-mutation of KRAS proto-oncogene (KRAS) and neurofibromin 1 genes had worse survival, and the underlying mechanism could be insufficient for protein synthesis and intracellular signal deactivation. Methylation of the Rac family small GTPase 1 (RAC1) was associated with better survival. The SNVs of the top mutated genes, including epidermal growth factor receptor (12.7%), neurotrophic receptor tyrosine kinase 3 (7.8%), erb-b2 receptor tyrosine kinase 4 (8.5%), and KRAS (29.6%), were associated with T cell exhaustion in LUAD. To construct nomograms, we further screened the genes whose genomic changes were closely associated with survival and immune infiltration. The nomograms performed well in predicting disease-specific survival (DSS) with a concordance index of 0.7 (0.589, 0.811) and overall survival with a concordance index of 0.689 (0.603, 0.775) in test set; they also showed good correspondence between actual and ideal nomogram predictions. Tumor stage, RAC1 methylation, and type 1 regulatory T cells greatly contributed to DSS and OS nomograms. In summary, we provided a comprehensive genomic profile of the RTK/RAS pathway in LUAD and its association with immune cell infiltration and prognosis of LUAD. This profile would serve as a basis for developing better therapeutic strategies, improving patient prognosis, and understanding the mechanisms of immune disturbance from the perspective of oncogenic pathways of LUAD.
RESUMO
BACKGROUND: Recently studies have demonstrated that the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) may participate in the development and progression of lung cancer. In this study, we hypothesized that genetic variant of this lncRNA may affect the prognosis of lung cancer patients. METHODS: We conducted a follow-up study for 538 patients with non-small cell lung carcinoma (NSCLC), including 140 early-staged (stage I and II) and 398 advanced staged (stage III and IV) patients. The genetic variant rs3200401 in MALAT1 was then genotyped among this population by using TaqMan assay. The association of this variant with overall survival of these patients was further analyzed. RESULTS: It was shown that among the advanced lung adenoma patients, subjects carrying rs3200401 CT and CT + TT genotypes had significantly longer median survival time (MST = 29.9, 28.9 vs. 19.3 month, Long-rank P = 0.019 and 0.024, respectively) and decreased death risks [crude HR (95% CI) = 0.65 (0.43-0.98) and 0.64 (0.44-0.95), P = 0.040 and 0.025, respectively], when compared to subjects wtih the MALAT1 rs3200401 CC genotype. However, the beneficial effect of rs3200401 was not seen among early NSCLC and advanced lung squamous cell carcinoma patients. We further tested the TCGA data, and found that a higher expression of MALAT1 was associated with metastatic of advanced lung adenocarcinoma but not with lung squamous cell carcinoma. CONCLUSIONS: The rs3200401 T allele located on the lncRNA MALAT1 was associated with a better survival for advanced lung adenocarcinoma patients, which may offer a novel prognostic biomarker for this patient subgroup. However, these results need to be validated in larger populations of lung cancer and the biological function of this variant still warrants further investigation.
